1296P BLU-945, a highly potent and selective 4th generation EGFR TKI for the treatment of EGFR T790M/C797S resistant NSCLC

Schalm, Stefanie; Dineen, Tom; Lim, Sung‐Jig; Park, C.W.; Hsieh, John; Woessner, Rich; Zhang, Z.; Wilson, Kevin; Eno, Meredith S.; Wilson, Douglas P.; Williams, Brett; Campbell, John E.; Savi, Chris De; Stevison, Faith; Utt, Caitlin; Guzi, Timothy J.; Dorsch, Marion; Hoeflich, Klaus P.; Cho, B.C.

doi:10.1016/j.annonc.2020.08.1610

Cited by 47 publications

(32 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To do so, plasma genotyping needs to be considered during the treatment, as well as tumor biopsy at progression to detect the ARM to the EGFR/BRAF/MEK pathway co-inhibition. Interestingly, an ARM to EGFR/BRAF/MEK pathway co-inhibition, with osimertinib as the EGFR TKI, may be the EGFR C797S mutation, which is potentially targetable with the fourth generation EGFR TKI BLU-945 [9,10,25,43].…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

Targeting BRAF Activation as Acquired Resistance Mechanism to EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small-Cell Lung Cancer

Nana

Ocak

2021

Pharmaceutics

View full text Add to dashboard Cite

Osimertinib has become a standard of care in the first-line treatment of advanced-stage non-small-cell lung cancer (NSCLC) harboring exon 19 and 21 activating mutations in the EGFR gene. Nevertheless, the 18.9-month median progression-free survival emphasizes the fact that resistance to osimertinib therapy is inevitable. Acquired resistance mechanisms to osimertinib in EGFR-driven NSCLC include MET amplification, EGFR C797S mutation, neuroendocrine differentiation, small-cell lung carcinoma histologic transformation, PD-L1 and KRAS amplifications and ESR1-AKAP12 and MKRN1-BRAF translocations, as well as BRAF V600 mutation. This last one represents 3% of the acquired resistance mechanisms to osimertinib. In this review, we discuss the rationale for EGFR/BRAF/MEK co-inhibition in the light of a clinical case of EGFR-mutant NSCLC developing a BRAF V600 mutation as an acquired resistance mechanism to osimertinib and responding to the association of osimertinib plus dabrafenib and trametinib. Additionally, we discuss the acquired resistance mechanisms to osimertinib plus dabrafenib and trametinib combination in that context.

show abstract

Section: Discussion and Perspectivesmentioning

confidence: 99%

Targeting BRAF Activation as Acquired Resistance Mechanism to EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small-Cell Lung Cancer

Nana

Ocak

2021

Pharmaceutics

View full text Add to dashboard Cite

show abstract

“… 162 , 163 BLU-945 is another fourth-generation EGFR-TKI targeting the T790M/C797S mutation reported in ESCO. 164 In vitro data suggested that BLU-945 achieved robust inhibition of Ex19del/T790M/C797S and L858R/T790M/C797S triple mutation, rather than EGFR WT . Cell-derived xenograft and patient-derived xenograft models consistently showed that single treatment with BLU-945 or coadministration with osimertinib/gefitinib significantly blocked the progression of tumors with the Ex19del/T790M/C797S mutation.…”

Section: Exploration Of Next-generation Egfr-tkismentioning

confidence: 98%

“… 162 L858R/T790M/C797S BBT-176 Bridge Bio Ex19del/T790M/C797S NA phase I Pharmabiz 163 L858R/T790M/C797S BLU-945 Blueprint Medicines Ex19del/T790M/C797S NA pre-clinical Schalm et al. 164 L858R/T790M/C797S Brigatinib a TAKEDA Pharma Ex19del/T790M/C797S reversible FDA approved Uchibori et al. 103 L858R/T790M/C797S ATP competitive a Multiple-target inhibitor.…”

Section: Exploration Of Next-generation Egfr-tkismentioning

confidence: 99%

Acquired resistance to third-generation EGFR-TKIs and emerging next-generation EGFR inhibitors

Yang

et al. 2021

The Innovation

View full text Add to dashboard Cite

Summary The discovery that mutations in the EGFR gene are detected in up to 50% of lung adenocarcinoma patients, along with the development of highly efficacious epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), has revolutionized the treatment of this frequently occurring lung malignancy. Indeed, the clinical success of these TKIs constitutes a critical milestone in targeted cancer therapy. Three generations of EGFR-TKIs are currently approved for the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). The first-generation TKIs include erlotinib, gefitinib, lapatinib, and icotinib; the second-generation ErbB family blockers include afatinib, neratinib, and dacomitinib; whereas osimertinib, approved by the FDA on 2015, is a third-generation TKI targeting EGFR harboring specific mutations. Compared with the first- and second-generation TKIs, third-generation EGFR inhibitors display a significant advantage in terms of patient survival. For example, the median overall survival in NSCLC patients receiving osimertinib reached 38.6 months. Unfortunately, however, like other targeted therapies, new EGFR mutations, as well as additional drug-resistance mechanisms emerge rapidly after treatment, posing formidable obstacles to cancer therapeutics aimed at surmounting this chemoresistance. In this review, we summarize the molecular mechanisms underlying resistance to third-generation EGFR inhibitors and the ongoing efforts to address and overcome this chemoresistance. We also discuss the current status of fourth-generation EGFR inhibitors, which are of great value in overcoming resistance to EGFR inhibitors that appear to have greater therapeutic benefits in the clinic.

show abstract

“…The 4th generation of EGFR TKIs, including EAI045 and BLU-945, are currently being studied to overcome C797S which is the most significant on-target resistance mechanism to osimertinib [ 28 ]. EAI045 is the first allosteric inhibitor that targets T790M and C797S EGFR mutations.…”

Section: Introductionmentioning

confidence: 99%

“…It has shown efficacy in combination with cetuximab in mouse models [ 29 ]. BLU-945 is another fourth-generation EGFR TKI that potently inhibits triple-mutant EGFR that harbors either activated L858R or exon 19 deletion mutations, plus acquired T790M and C797S mutations [ 28 ]. A Phase I/II, open-label, first-in-human (FIH) study NCT04862780 is recruiting to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anticancer activity of BLU-945 in EGFR-mutated NSCLC who have previously received at least 1 prior EGFR-targeted TKI including those with C797S mutation.…”

Section: Introductionmentioning

confidence: 99%

Targeted therapy in advanced non-small cell lung cancer: current advances and future trends

et al. 2021

View full text Add to dashboard Cite

Lung cancer remains the leading cause of cancer-related mortality in both men and women in the US and worldwide. Non-small cell lung cancer is the most common variety accounting for 84% of the cases. For a subset of patients with actionable mutations, targeted therapy continues to provide durable responses. Advances in molecular and immunohistochemical techniques have made it possible to usher lung cancer into the era of personalized medicine, with the patient getting individualized treatment based on these markers. This review summarizes the recent advances in advanced NSCLC targeted therapy, focusing on first-in-human and early phase I/II clinical trials in patients with advanced disease. We have divided our discussion into different topics based on these agents' mechanisms of action. This article is aimed to be the most current review of available and upcoming targeted NSCLC treatment options. We will also summarize the currently available phase I/II clinical trial for NSCLC patients at the end of each section.

show abstract

1296P BLU-945, a highly potent and selective 4th generation EGFR TKI for the treatment of EGFR T790M/C797S resistant NSCLC

Cited by 47 publications

References 0 publications

Targeting BRAF Activation as Acquired Resistance Mechanism to EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small-Cell Lung Cancer

Targeting BRAF Activation as Acquired Resistance Mechanism to EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small-Cell Lung Cancer

Acquired resistance to third-generation EGFR-TKIs and emerging next-generation EGFR inhibitors

Targeted therapy in advanced non-small cell lung cancer: current advances and future trends

Contact Info

Product

Resources

About